Retinoid-related orphan receptors (RORs) are transcription factors that form a subgroup of the nuclear receptor superfamily (Adv. Dev. Biol. 2006, 16, 313-355). This subgroup consists of three members: ROR alpha (RORα), ROR beta (RORβ) and ROR gamma (RORγ). RORα and RORβ have approximately 55% homology in the ligand binding domains to RORγ. RORs contain four principal domains shared by the majority of nuclear receptors: an N-terminal A/B domain, a DNA-binding domain, a hinge domain and a ligand binding domain.
The RORα, RORβ and RORγ genes have been mapped to human chromosomes 15q22.2, 9q21.13 and 1q21.3, respectively. Each ROR gene generates several isoforms, which differ only in their N-terminal A/B domain. To date, five splice variants have been recorded for RORγ and two isoforms of this member of the ROR family have been identified: RORγ1 and RORγ2 (also known as RORγt). RORγ is a term used to describe RORγ1 and/or RORγt.
While RORγ1 is expressed in a variety of tissues including thymus, muscle, kidney and liver, RORγt is exclusively expressed in the cells of the immune system and has a critical role in thymopoiesis, development of several secondary lymphoid tissues and Th17 lineage specification.
RORγt has been identified as a key regulator of Th17 cell differentiation (A. Jetten, Nuclear Receptor Signalling 2009, 7, 1-32). Th17 cells are a recently discovered subset of T helper cells which preferentially produce cytokines IL-17A, IL-17F, IL-21 and IL-22. RORγt also induces transcription of the gene encoding IL-17A and IL-17F in naïve CD4+ T helper cells, iNKT and NKT (Mucosal Immunol. 2009, 2(5), 383-392; J. Immunol. 2008, 180, 5167-5171), γδT cells (Am. J. Respir. Crit. Care Med. 2010, 182, 464-476), CD8+ T cells (J. Leukocyte Biol. 2007, 82, 354-360) and finally CD4−CD8−TCRαβ+ T cells (J. Immunol. 2008, 181, 8761-8766). Additional immune cells such as eosinophils, neutrophils and macrophages can also be a source of IL-17A in allergic inflammation related to asthma (J. Allergy Clin. Immunol. 2001, 108, 430-438; J. Immunol. 2008, 181, 6117-6124; Immunity 2004, 21, 467-476).
Th17 cells and their products have been shown to be associated with the pathology of a number of human inflammatory and autoimmune disorders. IL-17A and IL-17F are implicated in numerous immune and inflammatory responses primarily as pro-inflammatory regulators inducing the expression of cytokines, chemokines, adhesion molecules, mucin genes and growth factors. There is emerging evidence that an increase in IL-17A level is closely associated with a range of chronic inflammatory diseases such as rheumatoid arthritis (Curr. Opin. Investig. Drugs 2009, 10, 452-462), multiple sclerosis (Allergol. Int 2008, 57(2), 115-120), inflammatory bowel diseases (J. Inflamm. Res. 2010, 3, 33-44), uveitis, psoriasis (Sci. Transl. Med. 2010, 2(52)) and lung diseases (Prog. Respir. Res. Basel 2010, 39, 141-149; Resp. Research 2010, 11 (78), 1-11).
There is considerable evidence suggesting that Th17 cells/IL-17 play a key role in the pathogenesis of asthma. In asthmatic patients, both RORγt and IL-17A expression levels have been shown to be increased in sputum (Chin. Med. J. 2005, 118, 953-956; Resp. Res. 2006, 7(135), 1-9), lung (J. Allergy Clin. Immunol. 2003, 111(6), 1293-1298), bronchoalveolar lavage (BAL) fluids and peripheral blood (Immunol. Invest. 2009, 38, 652-664; Int. Arch. Allergy Immunol. 2005, 137 (suppl. 1), 51-54) and levels directly correlate with disease severity (Int. Arch. Allergy Immunol. 2010, 151, 297-307). In addition to IL-17A, a recent study has shown that a further cytokine of the IL-17 family, IL-17F, may have a crucial role in allergic airway inflammation and hence have key implications in airway diseases, such as asthma. The overexpression of the IL-17F gene in mice airways was associated with airway neutrophilia, cytokine induction, an increase in airway hyperreactivity and mucus hypersecretion (Inflamm. Allergy Drug Targets 2009, 8, 383-389). Evidence of role of Th17 cells in allergens has been discussed in Int. Immunopharmacol. 2010, 10, 226-229.
The pathogenesis of chronic autoimmune diseases including multiple sclerosis and rheumatoid arthritis arises from the break in tolerance towards self-antigens and the development of auto-aggressive effector T cells infiltrating the target tissues. Studies have shown that Th17 cells are one of the important drivers of the inflammatory process in tissue-specific autoimmunity (J. Exp. Med. 2008, 205, 1517-1522; Cell. Mol. Immunol. 2010, 7, 182-189). There is also evidence that Th17 cells are activated during the disease process and are responsible for recruiting other inflammatory cells types, especially neutrophils, to mediate pathology in the target tissues (Anna. Rev. Immunol. 2009, 27, 485-517). RORγt plays a critical role in the pathogenic responses of Th17 cells (Cell 2006, 126, 1121-1133). RORγt deficient mice show very few Th17 cells. Further support for the role of RORγt in the pathogensis of autoimmune or inflammatory diseases can be found in the following references: Immunity 2007, 26, 643-654; Nat. Rev. Immunol 2006, 6, 205-217; J. Immunol. 2009, 183, 7169-7177; Brain Pathol. 2004, 14, 164-174; Brain 2007, 130, 1089-1104; Nat. Rev. Immunol. 2008, 8, 183-192.
In light of the role RORγ plays in the pathogenesis of diseases, it is desirable to prepare compounds that modulate RORγ activity and hence have utility in the treatment of inflammatory, metabolic and autoimmune diseases mediated by RORγ, such as the respiratory diseases asthma, chronic obstructive pulmonary disease (COPD) and bronchitis, allergic diseases including allergic rhinitis and atopic dermatitis, cystic fibrosis and lung allograph rejection.